RSS

PDB:2PJY

Protein Name

TGF-β3 - TGF-β receptor complex

Species

Human

Biological Context

Secreted polypeptides of the transforming growth factor (TGF)-β superfamily regulate diverse physiological function such as growth, differentiation, and programmed death of cells. TGF-β superfamily includes three subfamilies: (1) TGF-β family, (2) activin family, and (3) bone morphogenic protein (BMP) family.

fig1
Fig1. Signaling mechanism of TGF-β superfamily

Fig1. Signaling mechanism of TGF-β superfamily (Fig. 1)

A dimeric TGF-β superfamily ligand (protein complex) binds to two pairs of receptor serine/threonine kinases known as type I and type II. The ligand-receptor heteromeric complex formation activates type II receptor. The active type II receptor phosphorylates type I receptor. Phosphorylated type I receptor phosphorylates a cytosolic factor, receptor-regulated Smad (R-Smad). Phosphorylated R-Smad binds to common-regulator Smad (C-Smad) and translocates into nucleus. The nuclear Smad complex regulates the expression of target genes.

The list of ligand-receptor-smad relationship in three TGF-β superfamilies is summarized below (table1).

table1

fig2
Fig2. Ligand-receptor complex formation of TGF-β and BMP

Ligand-receptor complex formation of TGF-β and BMP (Fig. 2)

The steps in ligand-receptor complex formation of TGF-β and BMP are different from each other. On the one hand, TGF-β binds to two receptors in two-step manner: TGF-β binds to higher affinity TβRII at first and sequentially binds to lower affinity TβRI. On the other hand, BMP binds to two receptors in one-step manner: BMP binds to BMPRI and ActRII independently.

Structure Description

2pjy2pjy_x2pjy_y

fig3
Fig3. Comparison of TGF-β-receptor complex and BMP-2-receptor complex

Comparison of TGF-β-receptor complex and BMP-2-receptor complex (Fig. 3)

Both contain a dimeric ligand and two pairs of type I- and type II receptors. Although the overall structures seem to be similar, two structural bases are dramatically different: (1) interaction between ligand and type I receptor, (2) interaction between N terminal region of typeII receptor and type I receptor. These are critical for the two step ligand binding mode of TGF-β families.

fig4a fig4b
Fig4. Prehelix loop

Prehelix loop (Fig. 4)

The interaction between TGF-β and TβRI is distinct from that between BMP2 and BMPRI. In BMP2 complex, a flexible loop preceding the α3 helix of ligands, the prehelix loop, is formed by three amino acids (D53, H54, and L55). Although the prehelix loop has been proposed as the conserved recognition motif for type I receptors, TGF-β lacks the prehelix loop. This would be the reason for the low affinity of the free TGF-β to type I receptors.

fig5
Fig5. Prehelix extension

Fig5. Prehelix extension (Fig. 5)

Instead of prehelix loop, TGF-β3-TβRI interaction is mediated by the prehelix extension. TβRI and BMPRI are compared here. TβRI contains an additional five residues in a loop named prehelix extension. Superposition of the ligands shows that TβRI is rotated about 45 degrees relative to BMPRIA, allowing the prehelix extension of TβRI to dock against the TGF-β3.

fig6
Fig6. Interaction between typeII receptor and type I receptor

Interaction between typeII receptor and type I receptor (Fig. 6)

TβRII-TβRI interaction plays a critical role in recruitment of TβRI after formation of TGF-β- TβRII complex. There are two important interactions. The principle interaction is a hydrogen-bonded ion pair between TβRI Arg58 (R58) and TβRII Asp118 (D118) that anchors at the composite interface of the complex. Another interaction is between the N terminal region of TβRII and TβRI. Although the N terminal region of TβRII is flexible when TβRI does not exist, it becomes ordered and tethers TβRI after TβRI recruitment.

Protein Data Bank (PDB)

References

Source

Groppe, J. Hinck, C.S. Samavarchi-Tehrani, P. Zubieta, C. Schuermann, J.P. Taylor, A.B. Schwartz, P.M. Wrana, J.L. Hinck, A.P.; "Cooperative Assembly of TGF-beta Superfamily Signaling Complexes Is Mediated by Two Disparate Mechanisms and Distinct Modes of Receptor Binding"; Mol.Cell; (2008) 29:1-13.

Others

author: Daisuke Ino


Japanese version:PDB:2PJY